CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as alpha 5-nicotinic acetylcholine receptor (CHRNA5), have been reported to be implicated in tumor progression. However, the functional mechanism of CHRNA5 in HCC remains unclear. In this study, we explored the role of CHRNA5 in HCC and found that CHRNA5 expression was increased in human HCC tissues and positively correlated with the T stage (p < 0.05) and AJCC phase (p < 0.05). The KM plotter database showed that the high expression level of CHRNA5 was strongly associated with worse survival in HCC patients. Both in vitro and in vivo assays showed that CHRNA5 regulates the proliferation ability of HCC by regulating YAP activity. In addition, CHRNA5 promotes the stemness of HCC by regulating stemness-associated genes, such as Nanog, Sox2 and OCT4. Cell migration and invasion assays demonstrated that CHRNA5 significantly enhanced the metastasis of HCC by regulating epithelial-mesenchymal transition (EMT)-associated genes. Furthermore, we found that CHRNA5 regulates the sensitivity of sorafenib in HCC. Our findings suggest that CHRNA5 plays a key role in the progression and drug resistance of HCC, and targeting CHRNA5 may be a strategy for the treatment of HCC.